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Query: UMLS:C0027651 (tumor)
 685,946 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Leukocyte infiltration and necrosis are two biological phenomena associated with the development of neovascularization during the malignant progression of human astrocytoma. Here, we demonstrate expression of interleukin (IL)-8, a cytokine with chemotactic and angiogenic properties, and of IL-8-binding receptors in astrocytoma. IL-8 expression is first observed in low grade astrocytoma in perivascular tumor areas expressing inflammatory cytokines. In glioblastoma, it further localizes to oxygen-deprived cells surrounding necrosis. Hypoxic/anoxic insults on glioblastoma cells in vitro using anaerobic chamber systems or within spheroids developing central necrosis induced an increase in IL-8 messenger RNA (mRNA) and protein expression. mRNA for IL-8-binding chemokine receptors CXCR1, CXCR2, and the Duffy antigen receptor for chemokines (DARC) were found in all astrocytoma grades by reverse transcription/PCR analysis. In situ hybridization and immunohistochemistry localized DARC expression on normal brain and tumor microvascular cells and CXCR1 and CXCR2 expression to infiltrating leukocytes. These results support a model where IL-8 expression is initiated early in astrocytoma development through induction by inflammatory stimuli and later in tumor progression increases due to reduced microenvironmental oxygen pressure. Augmented IL-8 would directly and/or indirectly promote angiogenesis by binding to DARC and by inducing leukocyte infiltration and activation by binding to CXCR1 and CXCR2.
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PMID:Upregulation of interleukin 8 by oxygen-deprived cells in glioblastoma suggests a role in leukocyte activation, chemotaxis, and angiogenesis. 933 59

Chemokines contribute to the inflammatory response by selective attraction of various leukocytic cell types. Human GCP-2 was originally identified by amino acid sequence analysis as a CXC chemokine co-produced with IL-8 by osteosarcoma cells. Furthermore, the complete coding domain of human GCP-2 was disclosed by means of RT-PCR. Similarly, mouse GCP-2 was isolated from fibroblastoid and epithelial cells and completely identified by sequence analysis. Human and mouse GCP-2 share 61% identical amino acids. Both chemokines occur as multiple NH2-terminally truncated forms. The shorter forms of mouse, but not those of human, GCP-2 showed a higher neutrophil chemotactic potency and gelatinase B releasing capacity. Mouse GCP-2 was a more potent neutrophil activator than human GCP-2, natural mouse KC, and MIP-2. Human GCP-2 was not chemotactic for monocytes, lymphocytes, or eosinophils. Quantitative studies of mRNA expression in diploid fibroblasts revealed GCP-2 induction by IL-1beta. Human GCP-2 induced [Ca2+]i increase in neutrophils, which was reciprocally desensitized by IL-8, GROalpha, and ENA-78. Human GCP-2 induced [Ca2+]i increases and chemotactic responses in both CXCR1- and CXCR2-transfected cells. Finally, GCP-2 provoked neutrophil accumulation and plasma extravasation in rabbit skin. In humans, GCP-2 complements the activity of IL-8 as neutrophil chemoattractant and activator but it constitutes a major neutrophil chemokine in the mouse. GCP-2 induces neutrophil chemotaxis and activation but it might also contribute to detrimental tissue damage in sepsis, acute respiratory distress syndrome, acute hypersensitivity reactions, and autoimmune diseases. It might also influence the invasive capacity of GCP-2-secreting tumor cells.
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PMID:Granulocyte chemotactic protein-2 and related CXC chemokines: from gene regulation to receptor usage. 936 9

By reverse transcriptase-polymerase chain reaction, enzyme-linked immunosorbent assay, and immunohistochemistry, MGSA-alpha, -beta, -gamma, and CXCR2 mRNA expression and proteins are detected in 7 out of 10 human melanoma lesions. The biological consequence of constitutive expression of the MGSA/GRO chemokine in immortalized melanocytes was tested in SCID and nude mouse models. Continuous expression of MGSA/GRO-alpha, -beta, or -gamma in immortalized melan-a mouse melanocytes results in nearly 100% tumor formation for each of the clones tested, whereas clones expressing only the neomycin resistance vector form tumors <10% of the time. Moreover, antibodies to the MGSA/GRO proteins slow or inhibit the formation of tumors in the SCID mouse model and block the angiogenic response to conditioned medium from the tumor-producing clones. Transcription of the MGSA/GRO chemokines is regulated by an enhancesome-like complex comprised of the nuclear factor-kappaB (NF-kappaB), HMG(I)Y, IUR, and Sp1 elements. In Hs294T melanoma cells the half life of the IKB protein is shortened in comparison to normal retinal epithelial cells, facilitating the endogenous nuclear localization of NF-kappaB. We propose that this endogenous nuclear NF-kappaB, working in concert with the 115-kDa IUR-binding factor, promotes constitutive expression of MGSA/GRO genes.
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PMID:Mechanism and biological significance of constitutive expression of MGSA/GRO chemokines in malignant melanoma tumor progression. 936 13

Cytokines and chemokines play significant roles in the recruitment of leucocytes from the circulation and are therefore crucial determinants of inflammatory reactions and immunity. As knowledge of the actions of these agents and their regulatory mechanisms increases, so does the opportunity to devise pharmacological means of intervening in the activities of these molecules. It is now believed, for instance, that the actions of the classical pro-inflammatory cytokine interleukin (IL)-1 are inhibited by the expression and presentation of a 'decoy' receptor, which acts as a 'molecular trap' for IL-1. There is evidence to suggest that IL-6, formerly considered a purely anti-inflammatory cytokine, also has proinflammatory properties. Furthermore, regulation of the chemokine system, which can be achieved by regulating agonist production or altering the expression of chemokine receptors, has recently been demonstrated. These and other new findings, which may prove to have considerable relevance as regards current or future strategies for the treatment of inflammation, infection, neoplasia etc., are presented and discussed in this article.
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PMID:The interplay between primary and secondary cytokines. Cytokines involved in the regulation of monocyte recruitment. 937 74

We isolated human intercrine reduced in hepatomas (hIRH) as a mRNA whose expression was reduced in differential displays from human hepatocellular carcinoma. hIRH is equivalent to the alpha-chemokine SDF-1alpha/PBSF. We have previously demonstrated on Northern blot analysis that although hIRH mRNA expression is common in human normal tissues, it is absent from pre-malignant colonic adenomas and from 27 human malignant cell lines. However, there are no reports on the mRNA status of hIRH in other human cancers. The present study was designed to investigate semi-quantitatively the expression of hIRH/SDF-1alpha mRNA in hepatocellular carcinoma and digestive tract cancers by reverse transcription-polymerase chain reaction (RT-PCR). The expression of hIRH/SDF-1alpha in the majority of cancer tissues analyzed was markedly reduced compared with that in adjacent non-cancer tissue. RT-PCR was more sensitive than Northern blots in the detection of hIRH mRNA. The average (mean +/- SE) tumor/normal (T/N) ratio determined by RT-PCR was 0.40 +/- 0.07 in 10 pairs of hepatoma, 0.38 +/- 0.09 in 14 pairs of colon cancers, 0.43 +/- 0.07 in 10 pairs of esophageal cancers and 0.70 +/- 0.09 in 26 pairs of gastric cancers. As a control, the mean G3PDH T/N ratio was 1.16 +/- 0.06. The distribution of T/N ratios was significantly different between gastric cancer and the other cancers, but there was no correlation between hIRH/SDF-1alpha expression and clinicopathological characteristics in gastric cancer. Our findings demonstrate that hIRH/SDF-1alpha expression is reduced in the majority of gastrointestinal tumors.
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PMID:Reduced expression of the CXC chemokine hIRH/SDF-1alpha mRNA in hepatoma and digestive tract cancer. 939 42

Tumor infiltrate, predominantly constituted by lymphocytes, may represent an important prognostic factor in bronchioloalveolar carcinoma (BAC), in addition to tumor extension and histological type. In the present study, we determined the presence, the origin, and the prognostic importance of neutrophils that also participate in leukocyte infiltrates of BAC. Neutrophil alveolitis was determined immunohistochemically in both lung biopsies and bronchoalveolar lavage (BAL) fluid samples from 29 patients with histologically proved BAC. The local expression of interleukin (IL)-8 was determined by immunohistochemical and immunoenzymatic techniques. Neutrophil counts were analyzed in relation to the clinical outcome of patients by the Kaplan-Meier method and Cox's univariate and stepwise multivariate models. Lymphocytes and neutrophils dominated the inflammatory cell population in the lower respiratory tract of patients with BAC. Neutrophils were located mainly in the alveolar lumen and seldom in alveolar wall whereas lymphocytes were exclusively present in alveolar wall. A relationship was observed between the number of neutrophils and the level of IL-8 in BAL fluid suggesting the involvement of that chemokine in neutrophil recruitment. The tumor cells were the predominant cells that appeared to express IL-8 by immunolocalization. The presence of increased numbers of neutrophils was significantly associated with a poorer outcome in patients with BAC (P = 0.02). In a multivariate analysis, the neutrophil percentage in BAL fluid was an independent predictor of clinical outcome. The risk of death was increased substantially (rate ratio, 5.2; 95% confidence interval, 1.1 to 24.7) among patients with BAL neutrophil percentage of > or = 39% (median of the distribution) as compared with the others. In BAC, neutrophils accumulate in the alveolar lumen. Elaboration of IL-8 by tumor cells may be responsible for this event, which is associated with a significantly higher risk of death.
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PMID:Neutrophil alveolitis in bronchioloalveolar carcinoma: induction by tumor-derived interleukin-8 and relation to clinical outcome. 942 26

The 9E3/CEF4 gene codes for a chemokine that is highly homologous to human interleukin-8 and melanoma growth-stimulating activity/groalpha. These chemokines belong to a family of molecular mediators that are importantly involved in inflammation, wound healing, tumor development, and viral entry into cells. On the chorioallantoic membrane the 9E3 protein is chemotactic for monocyte/macrophages and lymphocytes and is angiogenic. In cultured chicken embryo fibroblasts, which have many of the properties of wound fibroblasts, the gene is stimulated by a variety of agents including oncogenes, growth factors, phorbol esters, and thrombin. The strong stimulation of 9E3 by thrombin in culture correlates well with the observation that in young chicks this gene is stimulated to very high levels in fibroblasts upon wounding and remains high throughout wound repair. Activation of 9E3 by thrombin: (i) occurs very rapidly, one minute exposure to thrombin is sufficient to initiate the signals necessary for gene activation; (ii) is independent of mitogenesis; (iii) operates through the proteolytically activated receptor for thrombin; (iv) is mediated by tyrosine kinases, including c-src and the epidermal growth factor (EGF) receptor, rather than Ser/Thr kinases such as protein kinase C and protein kinase A. Inhibition of either c-src or the EGF receptor tyrosine kinase inhibits the stimulation of 9E3 by thrombin. We show here for the first time that activation of the EGF receptor through a cell-surface receptor that does not have tyrosine kinase activity can lead to expression of an immediate early response gene which encodes for a secreted protein, a chemokine. This rapidly activated tyrosine kinase pathway may be a general stress response by which in vivo a localized cell population reacts to emergency situations such as viral infection, wounding, or tumor growth.
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PMID:Thrombin aivation of the 9E3/CEF4 chemokine involves tyrosine kinases including c-src and the epidermal growth factor receptor. 947 78

Monocyte chemotactic protein (MCP)-1 and MCP-2, two closely related CC chemokines, are important mediators of monocyte and lymphocyte migration. These chemokines are secreted by various normal cell types, including fibroblasts, epithelial cells, and leukocytes, as well as by tumor cells. After stimulation with different cytokines and cytokine inducers the MCP-2 production levels are always lower than those of MCP-1. In human diploid fibroblasts cytokines differentially regulate chemokine induction, interleukin (IL)-1beta and interferon (IFN)-gamma being potent stimuli of MCP-1 and MCP-2, respectively. Co-stimulation of fibroblasts by 10 U/mL IL-1beta and 20 ng/mL IFN-gamma resulted in a synergistic induction of MCP-2, whereas the combined effect on MCP-1 and IL-6 production was rather additive. These findings were confirmed at the mRNA level by Northern blot analysis. In contrast, in human MG-63 fibroblastoid cells and HEp-2 epithelial cells, selected for their poor responsiveness to IL-1beta and IFN-gamma, MCP-2 as well as MCP-1 and IL-6 were synergistically induced, yielding protein levels that were increased 3- to 30-fold above the additive levels. When IFN-beta was used as a co-stimulant of IL-1beta, a similar synergistic induction of MCP-1 and MCP-2 was measured both at the protein and the mRNA level. It can be concluded that, when synergy occurred, the MCP-1 and MCP-2 expression levels reached a comparable maximum, indicative for an equal contribution of these chemokines in normal and pathological conditions.
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PMID:Synergistic induction of MCP-1 and -2 by IL-1beta and interferons in fibroblasts and epithelial cells. 950 May 25

The ESb-MP cell line is the subclone of a highly malignant variant of murine methylcholanthrene-induced T lymphoma, ESb. When injected in vivo, ESb-MP cells metastasize to the kidney with high frequency, whereas a non-adherent variant, ESb cells, rarely form metastatic foci in the kidney. Our previous results showed that ESb-MP, but not ESb, cells were able to migrate in response to murine kidney-conditioned media (KCM). In an effort to characterize the tumor cell chemoattractant(s) produced by kidney cells, we found that the murine kidney mesangial cell line MES-13 released more chemotactic activity for ESb-MP cells than present in KCM. A major heparin-binding chemotactic activity was purified to homogeneity by sequential fast-performance liquid chromatography and reversed phase high-performance liquid chromatography. Amino acid sequencing of the formic acid-digested active fractions revealed that the purified protein was identical to murine MCP-1(JE) and its activity was neutralized by an anti-MCP-1(JE) antibody. Another chemokine, RANTES, was also purified from MES-13 cell supernatant. The chemotactic activity contained in the MES-13 cell supernatant and in murine KCM was neutralized in part by a combination of anti-MCP-1(JE) and anti-RANTES antibodies. We further examined the differences in the ESb-MP and ESb cells. Binding studies using a variety of radio-iodinated chemokines showed that although both ESb-MP and ESb cells expressed substantial levels of high-affinity binding sites for CC chemokines, only ESb-MP cells migrated in response to CC chemokines and these cells constitutively expressed higher levels of beta2 integrin adhesion protein CD11b than their parental ESb cells. CC chemokines also activated NFkappaB in ESb-MP but not in ESb cells. Our results indicate that CC chemokines selectively chemoattract and activate ESb-MP cells. Thus, locally produced chemokines, MCP-1(JE) and RANTES in particular, may contribute to the preferential metastasis of ESb-MP cells to the kidneys.
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PMID:Purification and identification of chemokines potentially involved in kidney-specific metastasis by a murine lymphoma variant: induction of migration and NFkappaB activation. 950 36

Chemokines are key players in inflammation and infection. Natural forms of the C-X-C chemokine granulocyte chemotactic protein-2 (GCP-2) and the C-C chemokine regulated on activation normal T cell expressed and secreted (RANTES), which miss two NH2-terminal residues, including a Pro in the penultimate position, have been isolated from leukocytes or tumor cells. In chemotaxis and intracellular calcium mobilization assays, the truncation caused a reduction in the specific activity of RANTES but not of GCP-2. The serine protease CD26/dipeptidyl-peptidase IV (CD26/DPP IV) could induce this observed NH2-terminal truncation of GCP-2 and RANTES but not that of the monocyte chemotactic proteins MCP-1, MCP-2 and MCP-3. No significant difference in neutrophil activation was detected between intact and CD26/DPP IV-truncated GCP-2. In contrast to intact natural RANTES(1-68), which still chemoattracts monocytes at 10 ng/ml, CD26/DPP IV-truncated RANTES(3-68) was inactive at 300 ng/ml and behaved as a natural chemotaxis inhibitor. Compared with intact RANTES, only a 10-fold higher concentration of RANTES(3-68) induced a significant Ca2+ response. Furthermore, RANTES(3-68) inhibited infection of mononuclear cells by an M-tropic HIV-1 strain 5-fold more efficiently than intact RANTES. Thus, proteolytic processing of RANTES by CD26/DPP IV may constitute an important regulatory mechanism during anti-inflammatory and antiviral responses.
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PMID:Amino-terminal truncation of chemokines by CD26/dipeptidyl-peptidase IV. Conversion of RANTES into a potent inhibitor of monocyte chemotaxis and HIV-1-infection. 951 14


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